Synergistic potentiation of in vivo antitumor activity of anti-human T-leukemia immunotoxins by recombinant alpha-interferon and daunorubicin.
In the present study, immunotoxins (ITs) containing ricin A chain (RA) and anti-human T leukemia monoclonal antibodies SN1 and SN2 were used with or without alpha-interferon (IFN) and/or daunorubicin (DNR) for in vivo tumor suppression. SN1 and SN2 are directed toward two unique human T-leukemia-associated cell surface antigens, TALLA and GP37, respectively. As the tumor model, we used nude mice bearing ascitic tumors of Ichikawa, a human T acute lymphoblastic leukemia cell line. In initial studies, we investigated the effect of the IT injection schedule on the efficacy of ITs in the in vivo suppression of the ascitic tumors. Four doses of 20 micrograms each of SN1-RA and SN2-RA completely suppress the tumor growth in 100% of the treated mice when the IT treatment is initiated either 1 or 2 days after tumor inoculation of 1.6 x 10(7) Ichikawa cells into the mice. Subsequently, we investigated the potentiating effects of IFN and DNR on the in vivo antitumor activity of ITs. To this end, we chose to initiate the treatment 4 days after the tumor inoculation when IT treatment alone is only partially effective. ITs (10 micrograms each of SN1-RA and SN2-RA) plus IFN (2 x 10(5) IU) or ITs plus IFN plus DNR (5 micrograms) completely suppress tumor growth in 100% of the treated mice while similar treatment with any one of the three agents is only partially effective. Similar treatment with ITs plus DNR or IFN plus DNR results in complete suppression of tumor growth in 80% of the treated mice. These results were reproducible in a repeated experiment. To gain information about the mechanisms involving the IFN potentiation of IT activity, we carried out several experiments. The cell surface expression of TALLA and GP37 was slightly augmented by the in vitro incubation of Ichikawa cells with IFN as measured by fluorescence-activated cell sorter analysis. The degree of the increase in either TALLA or GP37 was significantly smaller than that of HLA class I antigens in the same experiment. In in vitro experiments, IFN did not show any significant cytotoxic activity against Ichikawa cells or augment the cytotoxic activity of ITs against Ichikawa cells. On the other hand, injections of IFN into nude mice augmented activity of macrophages and NK cells; however, Ichikawa leukemia cells were rather resistant to the NK cell lysis.(ABSTRACT TRUNCATED AT 400 WORDS)
Yokota
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S
Department of Molecular Immunology, Roswell Park Memorial Institute, Buffalo, New York 14263.
Hara
H
H
Luo
Y
Y
Seon
B K
BK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002460:Cell Line; D003131:Combined Modality Therapy; D003630:Daunorubicin / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D007370:Interferon Type I / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins; D012276:Ricin / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D007370:Interferon Type I; D011994:Recombinant Proteins; D012276:Ricin; D003630:Daunorubicin